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Abstract Background Adipsin (complement factor D, CFD), as the first described adipokine, is well-known for its regulatory effects in diabetic cardiovascular complications. However, its role in diabetic hind-limb ischemia was not clarified. This study aimed to evaluate the possible therapeutic effect of Adipsin in hind-limb ischemia in type 2 diabetic mice and to elucidate the molecular mechanisms involved. Methods A high-fat diet and streptozotocin (HFD/STZ)-induced diabetic mouse model, and a transgenic mouse model with adipose tissue-specific overexpression of Adipsin (Adipsin-Tg) were employed. Hindlimb ischemia was established by femoral artery ligation, and blood flow recovery was monitored using Laser Doppler perfusion imaging. Molecular mechanisms underlying Adipsin-potentiated angiogenesis were examined using RNA sequencing and co-immunoprecipitation/mass spectrometry (Co-IP/MS) analyses. Results Adipsin expression was upregulated in non-diabetic mice following HLI, while suppressed in diabetic mice, indicating its potential role in ischemic recovery which is impaired in diabetes. Adipsin-Tg mice exhibited significantly improved blood flow recovery, increased capillary density, and enhanced muscle regeneration in comparison with non-transgenic (NTg) diabetic mice. Adipsin facilitated proliferation, migration, and tube formation of human umbilical vein endothelial cells (HUVECs) under hyperglycemic and hypoxic conditions. Additionally, it enhanced phosphorylation of AKT, ERK, and eNOS pathways both in vivo and in vitro. RNA sequencing and co-immunoprecipitation/mass spectrometry (Co-IP/MS) analyses identified that Adipsin promoted angiogenesis by interacting with SERBP1, which disrupted the binding of SERBP1 to SERPINE1 mRNA, resulting in reduced SERPINE1 expression and the subsequent activation of the VEGFR2 signaling cascade. Conclusions Adipsin promotes angiogenesis and facilitates blood perfusion recovery in diabetic mice with HLI by downregulating SERPINE1 through interaction with SERBP1. These findings elucidate a novel therapeutic potential for Adipsin in the management of PAD in diabetic patients, highlighting its role in enhancing angiogenesis and tissue repair.

Abstract Background Placental accreta spectrum (PAS) disorder with bladder involvement is found to be associated with severe maternal and neonatal morbidity.When planning surgery or other treatments, a diagnosis and assessment of the invasiveness of placenta accreta spectrum disorder with bladder involvement are crucial.The detection of the depth of villi invasion can be accomplished with both MRI and US.The advent of three-dimensional Crystal Vue provides details additional information for scanning abnorma issue. Purpose Our goal was to compare and assess the diagnostic accuracy of 2D US combined with the 3D Crystal Vue and MRI in case of placenta accreta spectrum (PAS) involving the bladder. Materials and methods 111 pregnancy patients between May 2019 and November 2023 at the First Affiliated Hospital of Anhui Medical University whether or not they had placenta previa were included in the study if they were diagnosed of having placenta increta (PI) or placenta percreta (PP).Both US and MRI were used to evaluate the pregnant women.Total 53 pregnant women were ultimately included in our analysis.53 patients were split into groups with and without bladder involvement. They underwent 2D US,3D Crystal Vue, and MRI.The visual features of every subject were noted. Next, we analyzed the fundamental information, associated medical history, pregnancy outcomes, and different US and MRI signals between the two groups. To determine the potential contributing factors of PAS complicated with bladder involvement, a univariate analysis was performed. A multivariable logistic regression analysis was performed to identify US and MRI findings predictive of bladder involvement in placenta accreta spectrum. Results Multiple logistic regression analysis found that the bridging vessels (OR, 31.76,95% CI, 1.64-614.31,p = 0.022) and the tramline sign “fully” obliterated on Crystal Vue feature (OR, 68.92;95%CI,6.76-702.35,p

Abstract Background We aimed to investigate the effect and underlying mechanism of titanium (Ti) implant on the polarization of macrophages and subsequent effects on the osteogenic differentiation of periodontal ligament stem cells (PDLSCs) and angiogenesis of human umbilical vein endothelial cells (HUVECs) affected by macrophages. Methods Firstly, the regulatory effect of Ti implant on macrophage polarization was investigated. Levels of M1 polarization markers and M2 polarization markers in macrophages were evaluated by immunofluorescence staining method and qPCR analysis. The osteogenic differentiation capacity of PDLSCs cultured with supernatants of macrophages of each group was evaluated by the Alizarin Red S (ARS) staining method and qPCR. Angiogenesis related genes were also evaluated in HUVECs cultured in supernatants of macrophages. To explore whether RNA m5C modification can modulate the effects of Ti implant on macrophage regulation of osteogenic differentiation and angiogenesis, we analyzed the main genes related to m5C in macrophages using RNA m5C dot blotting and qPCR methods. The interaction between NSUN2 and IRF4 was verified by m5C-RIP, RIP, and double-luciferase gene report experiments. Results Macrophages were activated as M1 macrophages under the interference of LPS, and macrophages attached to Ti implants were more easily activated as M2 macrophages under the action of LPS. Macrophages activated by Ti implant enhanced osteogenic differentiation of PDLSCs and angiogenesis of HUVECs. NSUN2 level was up-regulated in macrophages treated with LPS and was down-regulated by Ti implant. Over-expression of NSUN2 attenuated the effect of Ti implant on M1 polarization promotion of macrophages and enhanced the M2 polarization promotion of macrophages. Up-regulation of NSUN2 weakened the effects of Ti implant on promotion the capacity of macrophages on osteogenic differentiation of PDLSCs and angiogenesis of HUVECs. The KEGG analysis suggested that IRF4 was enriched in several inflammatory signaling pathways. Moreover, NSUN2 methylates IRF4 to affect the capacity of macrophages on osteogenic differentiation of PDLSCs and angiogenesis of HUVECs. Conclusions Taken together, macrophages of M1 type can be stimulated by Ti implants in vitro, promoting osteogenic differentiation of PDLSCs and angiogenesis in HUVECs through NSUN2-mediated methylation of IRF4.

Objective: The anterolateral thigh (ALT) flap is a multifunctional diaphyseal flap used to reconstruct head and neck defects. The location, destination, and source of the perforator vessels are crucial for developing a reasonable surgical plan. The small FOV technique can narrow the reconstruction field, increase image resolution, and enhance the spatial resolution of perforator vessels. The two-stage contrast injection method enhances peripheral vessel filling pressure. Multiplanar reformation (MPR) allows coronal reconstruction of the area of interest permitting observation of the distribution of the distal perforator vessels of the lateral circumflex femoral artery. Curved multiplanar reformation (CPR) generates a curved image of the perforator vessels by integrating the curved path of the perforator vessels with the volume-rendering image of the lateral circumflex femoral artery to determine the location and course of the perforator vessels. This study was performed to improve perforator flap vessel visualization using various computed tomography angiography (CTA) scanning and post-processing techniques. Methods: The study group consisted of 13 patients with head and neck tumor defects who underwent improved preoperative CTA scanning between January 2018 and August 2021 at our hospital’s Department of Otorhinolaryngology, Head and Neck Surgery. The control group included 13 patients with no significant lesions in the femoral artery or its branches who underwent non-spectral CT angiography of the bilateral lower extremity arteries between September 2020 and April 2023 at the Radiology Department of Beijing Friendship Hospital, Capital Medical University. Vascular imaging quality was subjectively scored, and the contrast-to-noise ratios (CNR) and signal-to-noise ratios (SNR) of the lateral circumflex femoral artery were objectively evaluated. Results: While SNR in the intervention group was slightly higher than that in the control group, no significant difference was observed between the two groups. The average CNR in the study group was 18.25±7.38, while that in the control group was 7.26±2.64. The CNR in the study group was significantly higher than that in the control group, with a statistically significant difference between the two groups. No significant difference in subjective image quality scores was observed between the study and control groups. All perforator vessels detected on preoperative CTA in the study group were confirmed intraoperatively. Conclusions: Comprehensive application of multiple techniques increased the contrast between the perforator vessels and surrounding tissues, resulting in satisfactory CT image quality. These methods improve the accuracy of image analysis and provide better technical support for clinicians in analyzing the location, course, and source of blood vessels.

Abstract Proton-exchange-membrane fuel cells demand highly efficient catalysts for the oxygen reduction reaction, and core-shell structures are known for maximizing precious metal utilization. Here, we reported a controllable “carbon defect anchoring” strategy to prepare Pt1Ni1@Pt/C core-shell nanoparticles with an average size of ~2.6 nm on an in-situ transformed defective carbon support. The strong Pt–C interaction effectively inhibits nanoparticle migration or aggregation, even after undergoing stability tests over 70,000 potential cycles, resulting in only 1.6% degradation. The stable Pt1Ni1@Pt/C catalysts have high oxygen reduction reaction mass activity and specific activity that reach 1.424 ± 0.019 A/mgPt and 1.554 ± 0.027 mA/cmPt 2 at 0.9 V, respectively, attributed to the optimal compressive strain. The experimental results are generally consistent with the theoretical predictions made by our comprehensive microkinetic model which incorporates essential kinetics and thermodynamics of oxygen reduction reaction. The consistent results obtained in our study provide compelling evidence for the high accuracy and reliability of our model. This work highlights the synergy between theory-guided catalyst design and appropriate synthetic methodologies to translate the theory into practice, offering valuable insights for future catalyst development.

Underwater exercise is becoming increasingly prevalent, during which brain function is necessary but is also at risk. However, no study has explored how prolonged exercise affect the brain in underwater environment. Previous studies have indicated that excessive exercise in common environment causes brain dysfunction but have failed to provide appropriate interventions. Numerous evidence has indicated the neuroprotective effect of hyperbaric oxygen preconditioning (HBO-PC). The objective of this study was to investigate the cognitive effect of prolonged underwater exercise (PUE) and to explore the potential neuroprotective effect of HBO-PC in underwater environment. Rats swimming for 3 h in a simulated hyperbaric chamber (2.0 ATA) was used to establish the PUE animal model and HBO-PC (2.5 ATA for 1, 3,5 times respectively) was administrated before PUE. The results demonstrated that PUE triggers anxiety-like behaviors, cognitive impairment accompanied by hippocampal dysfunction, microglia activation and neuroinflammation. Conversely, 3 HBO-PC rescued anxiety-like behaviors and cognitive impairment. Mechanistically, 3 HBO-PC reduced microglia activation and switched the activated microglia from a pro-inflammatory to neuroprotective phenotype. These findings illustrated that PUE induces anxiety-like behaviors and cognitive impairment and HBO-PC of proper frequency may provide an appropriate and less invasive intervention for protecting the brain in underwater exercise.

Abstract Oxidative stress (OS) is believed to be a significant factor in the decline of semen quality, with mitochondrial DNA copy number (mtDNAcn) serving as a sensitive biomarker for both semen quality and mitochondrial dysfunction resulting from oxidative stress. While glutathione S-transferases (GSTs) are commonly known as ‘antioxidant’ enzymes, there is ongoing debate regarding the relationship between GST genotypes and semen quality. In a study involving 568 male volunteers from the outpatient department of Puyang Reproductive Medicine Center, sperm mtDNAcn, semen quality, and GSTM1/GSTT1 genotypes were analyzed to investigate the potential link between GSTM1/GSTT1 gene variations and semen quality, as well as the impact of GSTs gene variations on the connection between sperm mtDNAcn and semen quality. Adjusting for variables such as age, BMI, smoking, and alcohol consumption, it was found that mtDNAcn was significantly correlated with decreased sperm concentration and total sperm count (b = − 0.109, − 0.128, respectively; P = 0.002, 0.001, respectively). GSTM1 was associated with progressive motility (OR 0.390, 95% CI 0.218, 0.697), Straight line velocity (VSL) (OR = 0.606, 95% CI 0.385, 0.953), and Straightness (STR) (OR 0.604, 95% CI 0.367, 0.994), while GSTT1 was linked to progressive motility (OR 0.554, 95% CI 0.324, 0.944) and Beat crossover frequency (OR 0.624, 95% CI 0.397, 0.982). The GSTT1 was found to moderate the relationship between mtDNAcn and sperm motility parameters linearity (LIN), STR, and Wobble (WOB), with additive interaction effects observed between GSTT1 and mtDNAcn on LIN, STR, and WOB (P for interaction = 0.008, 0.034, 0.010, respectively). Overall, this study suggests that GSTT1 and GSTM1 gene variations may play a role in sperm motility, with GSTT1 potentially influencing the impact of oxidative stress on sperm motility.

Abstract Offset responses are traditionally viewed as indicators of sound cessation. Here, we investigate offset responses to auditory click trains, examining how they are modulated by inter-click intervals (ICIs) and train duration. Using extracellular recordings and electrocorticography (ECoG) in non-human primates, alongside electroencephalography (EEG) in humans, we show that offset responses are significantly influenced by both ICI and train length, thereby establishing them as markers of temporal integration. We introduce the concept of the ‘Neuronal Integrative Window’ (NIW), defined as the temporal span during which neurons integrate stimuli to produce or modulate the temporal integration signal. Our data reveal that on the neuronal level, the auditory cortex (AC) exhibits a more expansive NIW than the medial geniculate body (MGB), integrating stimuli over longer durations and showing a preference for larger ICIs. Furthermore, our results indicate that offset responses could serve as potential biomarkers for neurological and psychiatric conditions, highlighted by their sensitivity to pharmacological modulation with ketamine. This study advances our understanding of auditory temporal processing and proposes a novel approach for assessing and monitoring brain health.

Fault slip rates are critical for understanding the evolution of active faults, earthquake recurrence, and crustal deformation. Yet variations in slip rate along the Haiyuan Fault Zone (HYFZ), a large-scale sinistral strike-slip fault in the northeastern margin of the Tibetan Plateau, remain disputed. Here, we investigate in detail late Quaternary and present-day fault slip rates for several segments across the HYFZ based on previously published geologic and geodetic (i.e. GNSS and InSAR) estimates. Our results reveal that the strike-slip rates increase from ~1.6±0.4–1.8±0.3 mm/a on the Halahu (HLH) fault to ~5.2±1.3–6.2±0.9 mm/a on the Lenglongling (LLL) and Jinqianghe (JQH) faults, then decrease to ~3.9±0.8–4.6±0.3 mm/a on the Maomaoshan (MMS) and Laohushan (LHS) faults, subsequently remain relatively constant (i.e. ~4.6±0.8–4.8±0.7 mm/a) on the Haiyuan (HY) fault (in narrow sense), and finally decrease to ~1.3±0.1–1.5±0.3 mm/a on the Liupanshan (LPS) fault, from west to east. These results indicate that the strike-slip rates on the LLL and JQH faults are highest and decrease toward fault tips along the HYFZ, approximating an asymmetrical bell-shaped distribution. Furthermore, geodetic (short-term) and geologic (long-term) slip rates are in general agreement, indicating that the slip rates were relatively constant in the recent geologic history. Despite the shallow creep on the LHS fault, the Tianzhu Seismic Gap, Tuolaishan (TLS), LLL, and LPS faults have a large locking depth, strain accumulation, and/or long seismic quiescence period, underscoring the substantial seismic hazard in these areas. Our study contributes to characterizing the total slip rate budget across the HYFZ and provides insight into further understanding of seismic hazard and regional crustal deformation.

This study aims to predict the migration time of toxic fumes induced by excavation blasting in underground mines. To reduce numerical simulation time and optimize ventilation design, several back propagation neural network (BPNN) models optimized by honey badger algorithm (HBA) with four chaos mapping (CM) functions (i.e., Chebyshev (Che) map, Circle (Cir) map, Logistic (Log) map, and Piecewise (Pie) map) are developed to predict the migration time. 125 simulations by the computational fluid dynamics (CFD) method are used to train and test the developed models. The determination coefficient (R2), the variance accounted for (VAF), the Willmott’s index (WI), the root mean square error (RMSE), the mean absolute percentage error (MAPE), and the sum of squares error (SSE) are utilized to evaluate the model performance. The evaluation results indicate that the CirHBA-BPNN model has achieved the most satisfactory performance by reaching the highest values of R2 (0.9945), WI (0.9986), VAF (99.4811%), and the lowest values of RMSE (15.7600), MAPE (0.0343) and SSE (6209.4), respectively. The wind velocity in roadway (Wv) is the most important feature for predicting the migration time of toxic fumes. Furthermore, the intrinsic response characteristic of the optimal model is implemented to enhance the model interpretability and provide reference for the relationship between features and migration time of toxic fumes in ventilation design.

The test capacity of hypersonic equipment is crucial to the development of hypersonic technology. However, the maximum Mach number simulated by conventional hypersonic wind tunnel is less than 10 currently due to the insufficient heater capacity. Considering the outstanding performance of arc heater in high-enthalpy wind tunnel, applying arc-heated high-enthalpy wind tunnel for conventional aerodynamic tests makes a breakthrough for increasing test Mach numbers. This paper presented the test of AGARD-B calibration model carried out in the arc-heated high-enthalpy wind tunnel of the China Academy of Aerospace Aerodynamics. The standard deviation of multiple repeated aerodynamic test results verified the self-consistency of test data and proved the stability of flow field. Accuracy of the test data was also certified through comparison and analysis with existing data from both foreign and domestic wind tunnels. This test demonstrated that the arc-heated high-enthalpy wind tunnel is fully capable of conducting aerodynamic tests at Mach 10.

Abstract Background Osteoporosis is a major health concern for postmenopausal women, and the effect of simvastatin (Sim) on bone metabolism is controversial. This study aimed to investigate the effect of simvastatin on the bone microstructure and bone mechanical properties in ovariectomized (OVX) mice. Methods 24 female C57BL/6J mice (8-week-old) were randomly allocated into three groups including the OVX + Sim group, the OVX group and the control group. At 8 weeks after operation, the L4 vertebral bones were dissected completely for micro-Computed Tomography (micro-CT) scanning and micro-finite element analysis (µFEA). The differences between three groups were compared using ANOVA with a LSD correction, and the relationship between bone microstructure and mechanical properties was analyzed using linear regression. Results Bone volume fraction, trabecular number, connectivity density and trabecular tissue mineral density in the OVX + Sim group were significantly higher than those in the OVX group (P

Abstract Prostate cancer (PCa) is a highly heterogeneous disease, encompassing various molecular and clinical pathological subtypes. Fusion genes play a facilitating role in the occurrence and progression of PCa. We categorized PCa samples into the ETS family of transcription factors fusion positive and fusion negative subtypes based on fusion genes. This subtyping method is closely related to the epigenomic DNA methylation profiles of PCa, with each sample cluster including more than 85% of the patients. We conducted an analysis of the distribution of the ETS family fusion genes on chromosomes, fusion modes within reading frames, and predictions of structural domains. Among these, the highest frequency of the ETS family related fusion genes occurred on chromosome 21. Compared to the parental genes, fusion genes exhibited new structural domains, such as IG_like, and the most common fusion mode was out-of-frame fusion. The correlation between the methylation levels of hypermethylated CpG sites and the expression levels of their corresponding mRNAs indicates that CD8A and B3GNT5 (with correlations of − 0.388 and − 0.253, respectively) could serve as potential prognostic markers for PCa.

Abstract Background Data on long-term cancer survivors treated with apatinib are lacking. This study aimed to describe the characteristics of long-term cancer survivors after apatinib-based therapy, and to know about their satisfaction degree with apatinib and severity of depression and insomnia. Methods Patients with solid tumors who had received apatinib-based therapy for at least 5 years were invited to complete an online questionnaire. Characteristics of patients and treatment, knowledge of apatinib, satisfaction degree, and severity of depression and insomnia assessed by Patient Health Questionnaire-9 and Insomnia Severity Index were collected. Results Between December 8, 2023 and March 1, 2024, a total of 436 patients completed the online questionnaire. Most patients were satisfied with the efficacy (96.6%) and safety (93.1%) of apatinib, were willing to continue apatinib treatment (99.5%), and would recommend apatinib to other patients (93.3%). Continuous apatinib treatment resulted in significant negative impact on daily life, work, or study in only two (0.5%) patients. Almost all patients currently had no or mild depression (97.0%) and insomnia (97.9%) problems. The most common patient-reported adverse events were hand-foot syndrome (21.3%) and hypertension (18.3%). Conclusions Our survey showed a high satisfaction degree with apatinib in long-term cancer survivors. Long-term apatinib treatment resulted in almost no negative impact on patient’s quality of life.

To examine how different harvesting periods affect the storage quality of 'Satsuma' plum fruits, this study analyzed 13 quality and physiological metrics post-harvest and utilized principal component analysis (PCA) and mathematical models to assess (0±0.5)℃ low temperature storage quality across three different harvesting periods (100 d after flowering, 103 d after flowering, 106 d after flowering). The results showed that harvesting at 103 days after full bloom led to the best preservation effect. Additionally, the hardness and total acidity of plum fruit decreased by 37.37% and 27.06% respectively until the end of the storage period, which was the slowest. Furthermore, changes in relative conductivity, anthocyanins, total soluble solids, malondialdehyde, total phenols, and flavonoids were relatively smooth. The activity of polyphenol oxidase was low, while peroxidase, superoxide dismutase, and catalase activities were high, specifically catalase activities. After conducting PCA analysis, it was determined that PC1, PC2, and PC3 accurately capture 87.472% of the relevant information. These results suggested that varying harvesting periods would have significant impacts on all indicators. The mathematical model analysis revealed that the plum fruits harvested at 100, 103, and 106 days after bloom, and stored for 56 days, had comprehensive scores of 1.06, 0.99, and 2.69, respectively. Lower comprehensive scores indicated better quality, so the order of preservation effect was as follows: 103 days after bloom>100 days after bloom>106 days after bloom. The study provides a theoretical framework for evaluating postharvest preservation and quality of plum fruits, along with technical parameters to enable timely harvesting.

The Chinese tongue sole (Cynoglossus semilaevis) belonging to Pleuronectiformes, Cynoglossidae, Cynoglossus, is distributed in the sea areas of Korea, Japan and China. C. semilaevis has limited natural resources and no long-distance migration, which is suitable for the development of aquaculture in coastal areas. After more than ten years of artificial domestication, C. semilaevis has become one of the main mariculture species. Water temperature is an important environmental factor affecting the growth and development of fish. High temperature in summer can cause stress and even death of C. semilaevis, which is one of the important factors affecting factory farming and the promotion in the southern coast. However, the physiological and molecular changes of C. semilaevis in response to acute high temperature stress was still unclear to date.When fish are stimulated by high temperature, it can cause oxidative stress, resulting in a variety of toxic effects. It has been found that there is a significant correlation between high temperature and the activity of antioxidant enzymes in many aquatic animals. Therefore, changes in the activities of antioxidant enzymes can be used as an important indicator when fish are in a state of oxidative stress under high temperature stress. As a tissue related to detoxification metabolism and immunity of fish, liver plays an important role in response to high temperature stress, thus the tissue structure and apoptosis are also important indicators of liver health status after high temperature stress. Heat shock proteins (HSPs) are a class of common biological stress proteins, which have biological functions such as anti-stress, anti-oxidation, and regulation of apoptosis. HSPs are also involved in the resistance of fish to heat stress. Recently, it has been found that zebrafish (Danio rerio) is extremely sensitive to temperature changes after knockout of dual-specificity phosphatase 1 (dusp1) gene, and dusp1 has the possibility of maintaining redox homeostasis, so it was speculated that dusp1 gene may plays an important role in fish resistance to heat stress. In this study, heat shock protein family A member 1A (hspa1a) in the heat shock protein HSP70 family, heat shock protein 90 beta family member 1 (hsp90b1) in the HSP90 family, and dusp1 gene were selected to study the temporal expression characteristics under high temperature stress.In order to explore the effects of high temperature stress on physiological and molecular changes in the liver of C. semilaevis, a full-sib family of C. semilaevis was selected as the experimental object to detect the oxidative damage and heat stress-related gene expressions. After continuous heating to high temperature stress conditions (35 ℃), liver tissues were collected at 0 h, 3 h, 6 h, 12 h and 24 h, respectively. Hematoxylin and eosin (HE) staining and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) were used to observe cell damage, antioxidant enzyme activity and malondialdehyde (MDA) content were measured, and the expression changes of stress-related genes hspa1a, hsp90b1 and dusp1 were detected. The results showed that acute high temperature stress could cause obvious pathological changes and apoptosis in the liver tissue of C. semilaevis. The activity of antioxidant enzyme superoxide dismutase (SOD), glutathione peroxidase (GPx), catalase (CAT) and the content of MDA in the high temperature stress group was significantly higher than that of the control group at 6 h, 12 h, 0 h and 24 h, respectively (P

ABSTRACT To date, complete genome sequences of 14 double-stranded RNA (dsRNA) phages are available, and studies have shown that the host range of dsRNA phages is limited. The hosts of most dsRNA phages belong to the genus Pseudomonas. However, the dsRNA phage phiNY, which has a non-lytic life cycle, was isolated from Microvirgula aerodenitrificans. Currently, the interaction between dsRNA phage phiNY and its host bacteria is unclear, which is not beneficial to a comprehensive understanding of dsRNA phage biology and the exploitation of dsRNA phage with non-lytic life cycle for biomedical applications and others. Phage adsorption is a crucial step through the interactions between receptor-binding protein (RBP) of the phage and its receptors to initiate the infection process, which dictates host range specificity. Thus, we identified the RBP and host receptor of phiNY. Through homology alignment, amino acid sequence similarity analysis, and the phylogenetic tree analysis, orf11, located in the M-segment of dsRNA phage phiNY, encodes a putative RBP. We further performed the whole-cell enzyme-linked immunosorbent assay (ELISA), western blotting assay, and indirect immunofluorescence assay and demonstrated that this orf11 is an RBP. Finally, using affinity chromatography, ELISA, and dynamic light scattering, we identified lipopolysaccharides (LPSs) on the surface of the host M. aerodenitrificans strain LH9 as host receptors involved in the adsorption of the dsRNA bacteriophage phiNY and observed the state of phiNY RBP after combining with LPS by atomic force microscopy. These results will guide future studies on phage-host interaction in a dsRNA phage with a non-lytic life cycle.IMPORTANCEThe interactions between the lytic dsRNA phages and their host receptors have been clarified in previous studies. However, the interaction between the dsRNA phage phiNY (which has a non-lytic life cycle) and its host receptors during the dsRNA phage adsorption process was unknown. Here, we found that phiNY uses the orf11 protein as a receptor-binding protein (RBP). In addition, we found that this orf11 recognizes lipopolysaccharide from the host bacterium Microvirgula aerodenitrificans strain LH9 as a specific receptor. These results suggest that phiNY, like lytic dsRNA phages, uses an RBP to bind to a similar host receptor (i.e., lipopolysaccharide). Determining the interaction between the dsRNA phage phiNY and its host receptors will help to elucidate the mechanisms underlying the phiNY non-lytic life cycle and enhance our understanding of its infection mechanism.

In this study, a strain isolated from the surface of flue-cured tobacco leaves, identified as Bacillus velezensis HJ-16, was applied in the solid-state fermentation of tobacco leaves. This strain, known for producing thermally stable enzymes, including amylase, cellulase, and protease, significantly improved the sensory qualities of tobacco, enhancing aromatic intensity, density, and softness, while reducing irritation. Whole-genome sequencing and functional annotation revealed that B. velezensis HJ-16 possesses a single circular chromosome containing genes associated with enzyme production and metabolic activities, particularly in carbohydrate metabolism and amino acid metabolism. Untargeted metabolomics analysis identified significant changes in non-volatile metabolites induced by fermentation. These metabolites were enriched in pathways related to flavonoid biosynthesis, alkaloid biosynthesis, aromatic amino acid metabolism, lipid metabolism, and carbon metabolism. Metagenomic analysis showed that Bacillus became the dominant genus on the tobacco leaf surface following inoculation with B. velezensis HJ-16, altering the microbial community composition, reducing diversity and evenness, and enhancing microbial metabolic activity. These findings underscore the potential of B. velezensis HJ-16 as a biotechnological tool to improve tobacco leaf quality.

Summary: Background: Adverse childhood experiences (ACEs) are common and associated with mental disorders. However, the prevalence and co-occurrence of ACEs and their association with mental health outcomes among Chinese adults have not been well demonstrated. Methods: China Mental Health Survey, a cross-sectional nationally representative survey consisting of 28,140 adults, was conducted from July 2013 to March 2015. Twelve ACEs and mental health outcomes, including mood disorder, anxiety disorder, substance-use disorder, and suicide were measured using the Composite International Diagnostic Interview (CIDI) 3.0 in a weighted representative subsample of 9378 respondents. Latent class analysis was used to identify the co-occurrence profiles of ACEs, and logistic regression was applied to examine the association between ACEs and mental health outcomes. Population-attributable fractions (PAFs) were calculated to quantify the attribution of ACEs to these outcomes. Findings: Among the 9378 respondents, the weighted count (proportion) of females was 4642 (49.5%), with a weighted mean (SD) age of 43.0 (15.8) years. In this study, 27.1% of respondents showed at least one ACE, with multiple ACEs common (37.6%) among those affected. Neglect was the most prevalent ACE (11.3%), followed by physical abuse (9.1%). Latent class analysis identified four co-occurrence profiles: low risk of ACEs, maltreatment, caregiver’s maladjustment and parental loss. The strongest association with mental health outcomes was found in the caregiver’s maladjustment group (OR, 4.9; 95% CI, 3.2–7.6). Estimates of PAFs indicated that all ACEs together explained 39.4% (95% CI, 31.3%–47.4%) of observed mental health outcomes. Gender differences were noted in prevalence and associations with outcomes. Interpretation: ACEs are highly prevalent and interrelated in China, attributing to over one-third of the mental disorder burden. In resource-limited settings, prioritizing the reduction of the most prevalent and impactful ACEs through education and policy can more effectively alleviate the disease burden. Funding: The National Twelfth Five-Year Plan for Science and Technology Support from the Chinese Ministry of Science and Technology (grant numbers 2012BAI01B01 & 2015BAI13B00), and the National Key R&D Program of China (grant numbers 2017YFC0907800 and 2017YFC0907801).

Abstract The safety and efficacy of the lipid nanoparticle (LNP) delivery system are crucial for the successful development of messenger RNA vaccines. We designed and synthesized a series of ketal ester lipids (KELs), featuring a biodegradable ketal moiety in the linker and ester segments in the tail. Through iterative optimization of the head and tail groups of KELs, we tuned the pKa and molecular shapes, and identified (4S)‐KEL12 as a safe and efficient ionizable lipid for mRNA delivery. (4S)‐KEL12 LNP showed significantly higher delivery efficacy and lower toxicity than the DLin‐MC3‐DMA LNP. In comparison to SM‐102 LNP, (4S)‐KEL12 LNP exhibited better spleen tropism, reduced liver tropism, and hepatotoxicity. Additionally, (4S)‐KEL12 demonstrated good biodegradability following intramuscular or intravenous injection. Notably, (4S)‐KEL12 LNP encapsulated with a therapeutic mRNA cancer vaccine elicited robust cellular immune responses leading to substantial tumor regression along with prolonged survival in tumor‐bearing mice. Our results suggest that (4S)‐KEL12 LNP holds great promise for mRNA vaccine delivery. The comprehensive analysis of the structure‐activity relationship, toxicity, biodegradability, distribution, expression, efficacy, and stereochemistry of these LNPs will greatly contribute to the rational design and discovery of novel lipid‐based delivery systems.

Summary: It remains incompletely understood how the astrocytes in the mediobasal hypothalamus (MBH) regulate systemic glucose and cholesterol metabolism. Here, we show that MBH astrocytic Tak1 (transforming growth factor β [TGF-β]-activated kinase 1) controls the metabolism of glucose and cholesterol. Tak1 is expressed in MBH astrocytes and activated after a short-term nutritional excess. In chow-fed mice, astrocytic deletion of Tak1 across the brain or its suppression in the MBH impairs glucose tolerance, reduces insulin sensitivity, and results in hypercholesterolemia. Astrocytic Tak1 activation in the MBH alleviates these symptoms in mice fed a high-fat diet (HFD). We show that astrocytic Tak1 modulates the activity of proopiomelanocortin (POMC) neurons and enables the transport of mitochondria from astrocytes to POMC neurons. In astrocytic Tak1 knockout mice, supplementation of CD38, a molecule that is crucial in mitochondrial transfer, restores glucose and cholesterol homeostasis. Overall, these findings highlight an important role of MBH astrocytic Tak1 in glucose and cholesterol metabolism.

Summary: Background: Excessive use of antibiotics is a widespread problem. We aim to evaluate the efficacy of a multifaceted intervention for reducing antibiotic use in patients with respiratory tract infections (RTIs). Methods: In this two-arm cluster randomized controlled trial, we enrolled patients aged 18+ with symptomatic RTIs at 40 township health centers (THCs) selected from 10 counties in Anhui, China. The THCs were randomized using an online tool (‘Sealed Envelope’) to intervention or usual care (1:1 ratio), stratified by baseline antibiotic prescribing and with random block sizes (4 or 6). The intervention had five components: a half-day clinician training, a WeChat-based peer support group, a decision aid, a poster commitment letter and a patient leaflet. The primary outcome was whether antibiotics were prescribed at the index consultation. Secondary measures included defined daily dose (DDD), illness recovery rate, re-visits to other care-givers or retail pharmacies and incremental cost-effectiveness ratio (ICER). These measures were analyzed using generalized linear mixed modeling controlling for clustering. The study was registered as ISRCTN30652037. Findings: Between December 2021 and September 2022, 1053 patients were recruited (intervention, 21 THCs, n = 552; control, 19 THCs, n = 501), using consecutive sampling. Antibiotic prescribing rate was 55.25% and 66.67% in the intervention and control arms (Odds ratio 0.52, 95% confidence interval [CI]: 0.27, 0.98; p = 0.044). The intervention group also had lower, significant or non-significant, differences for other markers of antibiotic use: DDD (1.57 vs 2.75); prescriptions of two or more types of antibiotics (9.78% vs 11.58%); obtaining antibiotics from retail pharmacies (3.68% vs 5.78) or from other clinics (2.70% vs 4.05%). The intervention resulted in a cost reduction of 9.265 RMB (1.471 USD) per consultation episode and an ICER of −7769.98 RMB or −1233.33 USD/QALYs. The intervention did not encounter any major adverse event. Interpretation: The intervention package was effective and cost-effective in reducing antibiotics prescribing without adverse effects. Funding: The trial was supported by National Natural Science Foundation of China (No. 81861138049) and United Kingdom Research Innovation (No. MR/S013717/1).

Death receptor-mediated extrinsic apoptosis system had been developed as a promising therapeutic strategy in clinical oncology, such as TRAIL therapy. However, multiple studies have demonstrated that TRAIL resistance is the biggest problem for disappointing clinical trials despite preclinical success. Targeting cellular FLICE inhibitory protein (cFLIP) is one strategy of combinatorial therapies to overcome resistance to DR-mediated apoptosis due to its negative regulator of extrinsic apoptosis. E × 527 (Selisistat) is a specific inhibitor of SIRT1 activity with safe and well tolerance in clinical trials. Here, we show that E × 527 could strengthen significantly activation of rhFasL-mediated apoptotic signaling pathway and increased apoptotic rate of T leukemia cells with high expression of cFLIP. Mechanically, Inhibition of SIRT1 by E × 527 increased polyubiquitination level of cFLIP via increasing acetylation of Ku70, which could promote proteosomal degradation of cFLIP protein. It implied that combinatorial therapies of E × 527 plus TRAIL may have a potential as a novel clinical application for TRAIL-resistant hematologic malignancies.

Introduction Advanced chronic kidney disease (CKD) is common among patients with coronary artery disease (CAD), and angiotensin‑converting enzyme inhibitors (ACEI) or angiotensin‑receptor blockers (ARB) can improve cardiac and renal function, but whether ACEI/ARB therapy improves long-term prognosis remains unclear among these high-risk patients. Therefore, this research aimed to investigate the relationship between ACEI/ARB therapy and long-term prognosis among CAD patients with advanced CKD.Methods CAD patients with advanced CKD were included in five hospitals. Advanced CKD was defined as estimated glomerular filtration rate (eGFR)

Ultra-high performance concrete prepared by calcium sulfoaluminate cement (CSAC-UHPC) possesses promising applications because of its excellent early strength, durability and environmental benefits. However, the impacts of supplementary cementitious materials (SCMs), an important components for UHPC, on the properties of CSAC-UHPC remain ambiguous in international research. To well complement this subject, effects of three ultra-fine SCMs, ground granulated blast furnace slag (GGBFS), limestone powder (LP) and silica fume (SF), on the properties of CSAC-UHPC were investigated, including flowability, setting time, hydration process, microstructure and mechanical strength. Results showed that the flowability of CSAC-UHPC increased with the GGBFS and LP content increasing, respectively, and decreased with the SF content increasing. Meanwhile, the addition of GGBFS, LP and SF had a limited regulation of the setting time, with the initial and final setting time between separately 13—26 min and 19—35 min, but it inhibited the hydration of CSAC-UHPC and reduced the total amount of hydration products, among which the effect was most pronounced by SF. Moreover, the replacement to cement with 10 % mass fraction of GGBFS, LP and SF, individually, could refine the pore structure of CSAC-UHPC, and further increasing the replacement rate was detrimental to the development of micromorphology. The content of GGBFS and LP should not exceed 10 % without compromising the mechanical strength of CSAC-UHPC, while SF was not suitable for addition. The flexural strength at 4 h of CSAC-UHPC with 10 % GGBFS and LP reached 8.1 MPa and 7.9 MPa, and the compressive strength at 4 h reached 49.4 MPa and 48.1 MPa, respectively. Also, they have a carbon footprint reduction of approximately 25—40 % and an embodied energy reduction of approximately 25—35 %, compared to ordinary UHPC.

Objective The aim of this study was to investigate the potential importance of complement system activation, with particular emphasis on the complement alternative pathway (AP), in the pathogenesis of hypertensive renal damage.Methods Serum complement C3, complement Factor H (CFH) and AP activation were assessed in 66 participants with established essential hypertension with renal damage (RD). Fifty-nine patients with age- and sex-matched essential hypertension without renal damage (NRD) and 58 healthy participants (normal) were selected.Results Our study revealed that C3 and AP50 continuously increased from normal to NRD to RD (p

ABSTRACTThis study employed sero-epidemiological methods to estimate the incidence of pertussis within a healthy population located in eastern China. The aim was to gain deeper insights into the epidemiological characteristics and burden of pertussis within the country. Blood samples were collected from healthy individuals in Jiangsu Province between June 2019 and December 2022. The levels of IgG antibodies against pertussis toxin (anti-PT) and filamentous hemagglutinin (anti-FHA) in the serum were quantitatively measured using enzyme-linked immunosorbent assay (ELISA). Additionally, pertussis case data reported in Jiangsu Province were collected from the China Information System for Disease Control and Prevention and compared with the results of this study. In 2022, the reported incidence of pertussis stood at 1.0 per 100,000 individuals, marking the highest rate observed in the past two decades. Among 1,909 patients examined, the geometric mean concentration (GMC) of anti-PT IgG antibody was 20.2 (18.5–21.9) IU/ml, while that of anti-FHA IgG antibody was 27.0 (25.4–28.7) IU/ml. The IgG-PT and IgG-FHA seropositivity rate (>20.0 IU/ml) was highest in the 1 ~ 2 y old group and decreased rapidly to the lowest in the 3 ~ 4 y old group and then increased gradually with age. The estimated rate of pertussis infection based on seroprevalence was approximately 25,625‐fold higher than the reported notification rate in the ≥15 year age group. Our findings highlight decreased immunity post-vaccination, stressing the importance of additional booster shots for adolescents and adults to maintain immunity and reduce severe illness. Additionally, they offer vital guidance for policymakers to enhance immunization strategies.

AbstractA new series of 1H-pyrrolo[3,2-c]pyridine derivatives were designed and synthesised as colchicine-binding site inhibitors. Preliminary biological evaluations showed that most of the target compounds displayed moderate to excellent antitumor activities against three cancer cell lines (HeLa, SGC-7901, and MCF-7) in vitro. Among them, 10t exhibited the most potent activities against three cancer cell lines with IC50 values ranging from 0.12 to 0.21 μM. Tubulin polymerisation experiments indicated that 10t potently inhibited tubulin polymerisation at concentrations of 3 μM and 5 μM, and immunostaining assays revealed that 10t remarkably disrupted tubulin microtubule dynamics at a concentration of 0.12 μM. Furthermore, cell cycle studies and cell apoptosis analyses demonstrated that 10t at concentrations of 0.12 μM, 0.24 μM, and 0.36 μM significantly caused G2/M phase cell cycle arrest and apoptosis. The results of molecular modelling studies suggested that 10t interacts with tubulin by forming hydrogen bonds with colchicine sites Thrα179 and Asnβ349. In addition, the prediction of physicochemical properties disclosed that 10t conformed well to the Lipinski’s rule of five.

Purpose To investigate the effects of canagliflozin (20 mg/kg) on Dahl salt-sensitive (DSS) rat gut microbiota and salt-sensitive hypertension-induced kidney injury and further explore its possible mechanism.Methods Rats were fed a high-salt diet to induce hypertension and kidney injury, and physical and physiological indicators were measured afterwards. This study employed 16S rRNA sequencing technology and liquid chromatography–tandem mass spectrometry (LC–MS/MS)-based metabolic profiling combined with advanced differential and association analyses to investigate the correlation between the microbiome and the metabolome in male DSS rats.Results A high-salt diet disrupted the balance of the intestinal flora and increased toxic metabolites (methyhistidines, creatinine, homocitrulline, and indoxyl sulfate), resulting in severe kidney damage. Canagliflozin contributed to reconstructing the intestinal flora of DSS rats by significantly increasing the abundance of Corynebacterium spp., Bifidobacterium spp., Facklamia spp., Lactobacillus spp., Ruminococcus spp., Blautia spp., Coprococcus spp., and Allobaculum spp. Moreover, the reconstruction of the intestinal microbiota led to significant changes in host amino acid metabolite concentrations. The concentration of uremic toxins, such as methyhistidines, creatinine, and homocitrulline, in the serum of rats was decreased by canagliflozin, which resulted in oxidative stress and renal injury alleviation.Conclusion Canagliflozin may change the production of metabolites and reduce the level of uremic toxins in the blood circulation by reconstructing the intestinal flora of DSS rats fed a high-salt diet, ultimately alleviating oxidative stress and renal injury.

Abstract Hematopoietic stem and progenitor cells (HSPCs) possess the potential to produce all types of blood cells throughout their lives. It is well recognized that HSPCs are heterogeneous, which is of great significance for their clinical applications and the treatment of diseases associated with HSPCs. This study presents a novel technology called Single‐Cell transcriptome Analysis and Lentiviral Barcoding (SCALeBa) to investigate the molecular mechanisms underlying the heterogeneity of human HSPCs in vivo. The SCALeBa incorporates a transcribed barcoding library and algorithm to analyze the individual cell fates and their gene expression profiles simultaneously. Our findings using SCALeBa reveal that HSPCs subset with stronger stemness highly expressed MYL6B, ATP2A2, MYO19, MDN1, ING3, and so on. The high expression of COA3, RIF1, RAB14, and GOLGA4 may contribute to the pluripotent‐lineage differentiation of HSPCs. Moreover, the roles of the representative genes revealed in this study regarding the stemness of HPSCs were confirmed with biological experiments. HSPCs expressing MRPL23 and RBM4 genes may contribute to differentiation bias into myeloid and lymphoid lineage, respectively. In addition, transcription factor (TF) characteristics of lymphoid and myeloid differentiation bias HSPCs subsets were identified and linked to previously identified genes. Furthermore, the stemness, pluripotency, and differentiation‐bias genes identified with SCALeBa were verified in another independent HSPCs dataset. Finally, this study proposes using the SCALeBa‐generated tracking trajectory to improve the accuracy of pseudo‐time analysis results. In summary, our study provides valuable insights for understanding the heterogeneity of human HSPCs in vivo and introduces a novel technology, SCALeBa, which holds promise for broader applications. Key points SCALeBa and its algorithm are developed to study the molecular mechanism underlying human HSPCs identity and function. The human HSPCs expressing MYL6B, MYO19, ATP2A2, MDN1, ING3, and PHF20 may have the capability for high stemness. The human HSPCs expressing COA3, RIF1, RAB14, and GOLGA4 may have the capability for pluripotent‐lineage differentiation. The human HSPCs expressing MRPL23 and RBM4 genes may have the capability to differentiate into myeloid and lymphoid lineage respectively in vivo. The legitimacy of the identified genes with SCALeBa was validated using biological experiments and a public human HSPCs dataset. SCALeBa improves the accuracy of differentiation trajectories in monocle2‐based pseudo‐time analysis.

Effective subunit vaccines for tuberculosis (TB) must target antigenic components at various stages of infection. In this study, we constructed fusion proteins using secreted antigens from Mycobacterium tuberculosis (M. tuberculosis), specifically ESAT6, CFP10, MPT64, and Rv2645 from the proliferation stage, along with latency-associated antigens Rv1738 and Rv1978. The resulting fusion proteins, designated LT33 (ESAT6-CFP10-Rv1738) and LT28 (MPT6461-170-Rv19788-60-Rv264521-80), were combined with an adjuvant containing dimethyldioctadecylammonium bromide (DDA), polyriboinosinic polyribocytidylic acid (PolyI:C), and cholesterol to construct subunit vaccines. We evaluated the subunit vaccine effect in C57BL/6 mice and revealed that LT33 and LT28 exhibited strong immunogenicity and induced protective efficacy against aerosol challenge with M. tuberculosis H37Rv. Notably, the combination of LT33 and LT28 led to a significant reduction of 0.77 log10 colony-forming units (CFU) of H37Rv in the lungs compared to the adjuvant control group, highlighting their potential as promising candidates for subunit vaccine against M. tuberculosis infection.

Summary: Background: Cancer cell plasticity is the ability of neoplastic cells to alter their identity and acquire new biological properties under microenvironmental pressures. In prostate cancer (PCa), lineage plasticity often results in therapy resistance and trans-differentiation to neuroendocrine (NE) lineage. However, identifying the cancer cells harboring lineage plasticity-related status remains challenging. Methods: Based on 13 multi-center human PCa bulk transcriptomic cohorts (samples = 3314) and 9 bulk transcriptomic datasets derived from PCa experimental models, we established an integrated lineage plasticity-related gene signature, termed LPSig. Leveraging this gene signature, AUCell enrichment analysis was applied to identify the cell population with high lineage plasticity from a comprehensive single-cell RNA-sequencing (scRNA-seq) meta-atlas assembled by us, which consisted of 10 public human PCa scRNA-seq datasets (samples = 93, cells = 222,529). Moreover, additional scRNA-seq dataset of human PCa, multiplex immunohistochemistry staining for human PCa tissues, in vitro and in vivo functional experiments, as well as qPCR and Western blot analyses were employed to validate our findings. Findings: We found that LPSig could finely capture the dynamics of tumor lineage plasticity throughout the progression of PCa, accurately estimating the status of lineage plasticity. Based on LPSig, we identified a previously undefined minority population of lineage plasticity-related PCa cells (LPCs) from the human PCa scRNA-seq meta-atlas assembled by this study. Furthermore, in-depth dissection revealed pivotal roles of LPCs in trans-differentiation, tumor recurrence, and poor patient survival during PCa progression. Furthermore, we identified HMMR as a representative cell surface marker for LPCs, which was validated using additional scRNA-seq datasets and multiplexed immunohistochemistry. Moreover, HMMR was transcriptionally inhibited by androgen receptor (AR), and was required for the aggressive adenocarcinoma features and NE phenotype. Interpretation: Our study uncovers a novel population of lineage plasticity-related cells with low AR activity, stemness-like traits, and elevated HMMR expression, that may facilitate poor prognosis in PCa. Funding: This work was supported by National Key R&D Program of China (2022YFA0807000), National Natural Science Foundation of China (82160584), Advanced Prostate Cancer Diagnosis and Treatment Technology Innovation Team of Kunming Medical University (CXTD202216), and Reserve Talents of Young and Middle-aged Academic Leaders in Yunnan Province (202105AC160013).

Recycling salt and water from saline wastewater is crucial for environmental preservation, resource conservation, and social economy sustainability. The heat pump air circulation evaporating separation (HP-ACES) system for saline wastewater treatment is proposed. Nevertheless, it is discovered that the system evaporation efficiency (SEE) is low and solid crystalline salt does not precipitate during the experiment. Therefore, an established and validated mathematical model of the HP-ACES system is provided and the average relative errors of the system evaporation rate (SER) and SEE are 5.3 % and 7 %, respectively. The theoretical analysis of the non-optimized system indicates that the main cause of the low SEE of the HP-ACES system during the test is incorrect cooling water flow. Hence, the system optimization scheme is presented and the comparison of the HP-ACES system's performances before and after optimization is conducted. Results demonstrate that the SEE of the optimized HP-ACES system has been greatly improved (optimized system: 0.62–2.46 kg/kWh, non-optimized system: 0.77–0.91 kg/kWh). Additionally, there is almost no change in the yield and composition of the solid crystalline salt when the inlet air temperature of spray separation tower is above 90 °C.

Summary: Background: Over 500,000 new cases are diagnosed with papillary thyroid cancer (PTC) globally per year, of whom the vast majority are in the low-risk stratification. Although thyroid-stimulating hormone (TSH) suppression is traditionally recommended for all postoperative PTCs in current guidelines, its necessity remains highly controversial in low-risk patients. Since relevant recommendations in current guidelines are still empirical, we aim to provide a direct, large-scale, real-world evidence. Methods: This large-scale real-world retrospective study included 11,140 low-risk PTC patients from two Chinese large-volume centers (Fudan University Shanghai Cancer Center [FUSCC] and Cancer Hospital of Chinese Academy of Medical Sciences [CH-CAMS]) treated from January 1, 2000 to June 30, 2022. The mean TSH level was calculated based on postoperative serum TSH values during follow-up. The primary outcome was the association between postoperative TSH level and structural recurrence assessed by Kaplan–Meier, log-rank, multivariate Cox regression analyses and equivalence testing by Two One-Sided Tests (TOST) procedure. Propensity score matching (PSM) was used to adjust for confounders among groups. Findings: A total of 11,140 patients with low-risk PTC were included with a median follow-up of 70 months. Based on the mean TSH level, we classified these patients into ≤0.5 (n = 1,504, 13.5%), (0.5–1] (n = 4,336, 38.9%), (1–2] (n = 4,285, 38.5%), (2–3] (n = 704, 6.3%) and >3 (n = 311, 2.8%) mU/L groups. After PSM adjusting for age, sex, T and N stage, 8991 patients were included in further analysis, for whom the log-rank analyses showed no significant differences between any two groups (all P > 0.05) in recurrence-free survival (RFS), locoregional recurrence-free survival (LRRFS) and distant metastasis-free survival (DMFS), and suppressed TSH was not associated with tumor recurrence in the multivariate Cox analysis (TSH > 2 group vs TSH ≤ 2 group: HR = 1.30, 95% CI = 0.85–2.01, P = 0.23). Furthermore, the TOST equivalence tests showed that tumor recurrence status of any two TSH groups were statistically comparable (all Bonferroni-corrected P values

Abstract Vibrio vulnificus, a significant marine pathogen, undergoes opaque (Op)-translucent (Tr) colony switching based on whether capsular polysaccharide (CPS) is produced. CPS phase variation is sometime accompanied by genetic variation or down-regulation of particular genes, such as wzb. In addition, CPS prevents biofilm formation and is important to the virulence of V. vulnificus. However, the extent to which there is a difference in gene expression between Tr and Op colonies and the impact of CPS phase variation on other behaviors of V. vulnificus remain unknown. In this work, the data have shown that CPS phase variation of V. vulnificus is affected by incubation time. Tr and Op strains exhibited similar growth rates. However, Tr strains had enhanced biofilm formation capacities but reduced swimming motility compared to Op strains. The RNA-seq assay revealed 488 differentially expressed genes, with 214 downregulated and 274 upregulated genes, between Tr and Op colonies. Genes associated with Tad pili and CPS were downregulated, whereas those involved in flagellum were upregulated, in Tr colonies compared with Op colonies. In addition, 9 putative c-di-GMP metabolism-associated genes and 28 genes encoding putative regulators were significantly differentially expressed, suggesting that CPS phase variation is probably strictly regulated in V. vulnificus. Moreover, 8 genes encoding putative porins were also differentially expressed between the two phenotypic colonies, indicating that bacterial outer membrane was remodeled during CPS phase variation. In brief, this work highlighted the gene expression profiles associated with CPS phase variation, but more studies should be performed to disclose the intrinsic mechanisms in the future.

Face stability is an essential issue in tunnel design and construction. Layered rock masses are typical and ubiquitous; uncertainties in rock properties always exist. In view of this, a comprehensive method, which combines the Upper bound Limit analysis of Tunnel face stability, the Polynomial Chaos Kriging, the Monte-Carlo Simulation and Analysis of Covariance method (ULT-PCK-MA), is proposed to investigate the seismic stability of tunnel faces. A two-dimensional analytical model of ULT is developed to evaluate the virtual support force based on the upper bound limit analysis. An efficient probabilistic analysis method PCK-MA based on the adaptive Polynomial Chaos Kriging metamodel is then implemented to investigate the parameter uncertainty effects. Ten input parameters, including geological strength indices, uniaxial compressive strengths and constants for three rock formations, and the horizontal seismic coefficients, are treated as random variables. The effects of these parameter uncertainties on the failure probability and sensitivity indices are discussed. In addition, the effects of weak layer position, the middle layer thickness and quality, the tunnel diameter, the parameters correlation, and the seismic loadings are investigated, respectively. The results show that the layer distributions significantly influence the tunnel face probabilistic stability, particularly when the weak rock is present in the bottom layer. The efficiency of the proposed ULT-PCK-MA is validated, which is expected to facilitate the engineering design and construction.

Abstract Due to the spectrum and complexity efficiency, the integrated radar and communications (RadCom) systems have been widely favored, in which orthogonal frequency division multiplexing (OFDM) is the most popular signal to conduct the two functions simultaneously. However, an unoptimized pulse could suffer from severe inter-carrier interference (ICI) and high out-of-band emission (OOBE), which greatly degrades the system performance. In this paper, we introduce the pulse shaping scheme dedicated to RadCom systems, in which both transmitter and receiver can adaptively design pulses with the assistance of radar estimation. We first optimize the transmitting pulse with the weighted sum of signal-to-interference-plus-noise ratio (SINR) and OOBE by employing the popular genetic algorithm. Then, we design an improved-matched pulse at the receiver for maximizing the SINR with the fmincon solver. In this way, they both utilize the readily available radar information and keep the pulse optimal even in highly dynamic scenarios, which makes the most of RadCom systems while avoiding the overhead of channel estimation and feedback. Simulations prove the feasibility of proposed scheme and reveal that the radar image and communications SINR stay close to their optimum in most cases with much lower OOBE. An improved-matched pulse can further improve the communications performance when severe ICI occurs compared with a matched pulse.

Abstract Background Canine enteric coronavirus (CECoV) is a prevalent infectious disease among dogs worldwide, yet its epidemiology in mainland China remains poorly understood. This systematic review and meta-analysis aimed to assess the prevalence of CECoV in mainland China and identify factors influencing its prevalence. Methods A comprehensive literature search was conducted across multiple databases for studies regarding CECoV epidemiology of China. PubMed, CNKI, Wanfang, and CQVIP were searched to obtain the studies. Eligible studies were selected based on predefined criteria, and data were extracted and synthesized. The quality the studies was assessed using the JBI assessment tool. Heterogeneity was checked using I2 test statistics followed by subgroup and sensitivity analysis. Subgroup analyses were performed to explore variations in CECoV prevalence by factors such as year, region, season, health status, social housing type, gender, age, and breed. Publication bias was assessed using a funnel plot and eggers test that was followed by trim and fill analysis. Results A total of 27 studies involving 21,034 samples were included in the meta-analysis. The overall pooled prevalence of CECoV in mainland China was estimated to be 0.30 (95% CI 0.24–0.37), indicating persistent circulation of the virus. Subgroup analyses revealed higher prevalence rates in younger dogs, multi-dog households, apparently healthy dogs, and certain regions such as southwest China. Seasonal variations were observed, with lower prevalence rates in summer. However, no significant differences in prevalence were found by gender. Conclusions This study provides valuable insights into the epidemiology of CECoV in mainland China, highlighting the persistent circulation of the virus and identifying factors associated with higher prevalence rates. Continuous monitoring and surveillance efforts, along with research into accurate detection methods and preventive measures, are essential for the effective control of CECoV and mitigation of its potential impact on animal and human health.

Abstract Background Percutaneous coronary intervention (PCI) with primary stenting, which stands for stent implantation regardless of obtaining satisfactory results with balloon angioplasty, has superseded conventional plain old balloon angioplasty with provisional stenting. With drug-coated balloon (DCB), primary DCB angioplasty with provisional stenting has shown non-inferiority to primary stenting for de novo coronary small vessel disease. However, the long-term efficacy and safety of such a strategy to the primary stenting on clinical endpoints in de novo lesions without vessel diameter restrictions remain uncertain. Study design The REC-CAGEFREE I is an investigator-initiated, multicenter, randomized, open-label trial aimed to enroll 2270 patients with acute or chronic coronary syndrome from 43 interventional cardiology centers in China to evaluate the non-inferiority of primary paclitaxel-coated balloons angioplasty to primary stenting for the treatment of de novo, non-complex lesions without vessel diameter restrictions. Patients who fulfill all the inclusion and exclusion criteria and have achieved a successful lesion pre-dilatation will be randomly assigned to the two arms in a 1:1 ratio. Protocol-guided DCB angioplasty and bailout stenting after unsatisfactory angioplasty are mandatory in the primary DCB angioplasty group. The second-generation sirolimus-eluting stent will be used as a bailout stent in the primary DCB angioplasty group and the treatment device in the primary stenting group. The primary endpoint is the incidence of Device-oriented Composite Endpoint (DoCE) within 24 months after randomization, including cardiac death, target vessel myocardial infarction, and clinically and physiologically indicated target lesion revascularization. Discussion The ongoing REC-CAGEFREE I trial is the first randomized trial with a clinical endpoint to assess the efficacy and safety of primary DCB angioplasty for the treatment of de novo, non-complex lesions without vessel diameter restrictions. If non-inferiority is shown, PCI with primary DCB angioplasty could be an alternative treatment option to primary stenting. Trial registration Registered on clinicaltrial.gov (NCT04561739).

Slope stability analysis plays a crucial role in geotechnical engineering, particularly in regions susceptible to seismic activity. The inherent non-homogeneity and uncertainty of soil properties pose significant challenges in assessing slope stability under seismic conditions. To address these complexities, a novel and efficient methodology named DUBLA-PDM-PCK is proposed. In this methodology, the effects of soil non-homogeneity and uncertainty, along with the time and spatial variations of seismic loading, are systematically considered. The deterministic framework integrates discretized upper bound limit analysis (DUBLA) to accommodate soil non-homogeneous characteristics, and the pseudo-dynamic method (PDM) to model seismic loading variability. Then, a robust and efficient probabilistic analysis method, PCK-MA, is implemented utilizing adaptive Polynomial Chaos Kriging metamodeling, Monte Carlo Simulation, and Analysis of Covariance to investigate the uncertainty of the parameters. This approach treats nine key parameters, including soil cohesion, friction angle, non-homogeneous coefficients, horizontal and vertical seismic coefficients, period, and amplification factor, as random variables to assess their uncertainty effects on failure probability (stability level) and sensitivity indices. The DUBLA-PDM-PCK methodology offers a streamlined and reliable tool tailored for assessing slope stability in seismic environments, demonstrating notable efficiency in addressing soil variability and seismic loading uncertainties. Its application holds promise for guiding engineering practices and enhancing understanding of slope behavior in regions prone to seismic hazards.

Abstract Glyphosate, widely used to manage weeds in cassava crops, simultaneously inhibits cassava growth, necessitating the development of herbicide-tolerant cassava varieties. In this study, screened 262 cassava varieties, identifying the glyphosate-resistant (GR) variety ZM8701 and the glyphosate-sensitive (GS) variety SC9. Transcriptomic analysis via Illumina sequencing revealed differentially expressed genes associated with resistance, including Cytochrome P450, GST, GT, ABC transporters, and others such as MIOX1, LHCA1, PPH, HSP26, HSP83A, and UGT73C5. Notably, the EMB3004 gene, involved in the biosynthesis of aromatic amino acids, was significantly upregulated in resistant varieties, suggesting a key role in countering glyphosate’s inhibition of the shikimic acid pathway. These genes are pivotal in enhancing cell wall biosynthesis, optimizing photosynthesis, and improving detoxification processes. This research elucidated the molecular mechanisms underlying cassava’s resistance to glyphosate, thereby laying the groundwork for breeding programs aimed at developing herbicide-resistant varieties. Graphical Abstract

Abstract The systemic immune-inflammation index (SII), an integrated and ground-breaking inflammatory measure, has been widely used in various fields. We aimed to assess the association between the systemic immune-inflammation index (SII) and α-Klotho (a new anti-aging biomarker). In this cross-sectional investigation, people with complete information on SII and α-Klotho from the National Health and Nutrition Examination Survey (NHANES) between 2007 and 2016 were the study's subject population. SII was calculated by platelet count × neutrophil count/lymphocyte count. The association between SII and α-Klotho was investigated using multivariable linear regression and a generalized additive model. In order to explore the non-linear connection, we employed smoothed curve fitting. Subgroup analysis were also performed. A total of 13,701 participants with an average age of 57.73 ± 10.86 years were enrolled, of whom 51.53% were female. After fully adjustment, SII was negatively associated with serum soluble α-Klotho [β(95% CI) = − 0.07 (− 0.08, − 0.05)]. Furthermore, we found L-shaped association between SII and klotho protein level, with the inflection point at 255 pg/ml. Subgroup analysis and interaction test revealed that there was no discernible dependence on gender, age, race, smoking, alcohol, diabetes and hypertension (all p for interaction > 0.05). SII level was negatively associated with serum klotho protein concentration in American adults. To verify our findings, more large-scale prospective investigations are still required.

Aspergillus niger is an efficient cell factory for organic acids production, particularly l-malic acid, through genetic manipulation. However, the traditional method of collecting A. niger spores for inoculation is labor-intensive and resource-consuming. In our study, we used the CRISPR-Cas9 system to replace the promoter of brlA, a key gene in Aspergillus conidiation, with a xylose-inducible promoter xylP in l-malic acid-producing A. niger strain RG0095, generating strain brlAxylP. When induced with xylose in submerged liquid culture, brlAxylP exhibited significant upregulation of conidiation-related genes. This induction allowed us to easily collect an abundance of brlAxylP spores (>7.1 × 106/mL) in liquid xylose medium. Significantly, the submerged conidiation approach preserves the substantial potential of A. niger as a foundational cellular platform for the biosynthesis of organic acids, including but not limited to l-malic acid. In summary, our study offers a simplified submerged conidiation strategy to streamline the preparation stage and reduce labor and material costs for industrial organic acid production using Aspergillus species.

Numerous analytical models have been developed to predict ground deformations induced by tunneling, which is a critical issue in tunnel engineering. However, the accuracy of these predictions is often limited by errors and uncertainties resulting from model selection and parameter fittings, given the paucity of monitoring data in field settings. This paper proposes a novel approach to estimate tunnelling-induced ground deformations by applying Bayesian model averaging to several representative prediction models. By accounting for both model and parameter uncertainties, this approach enables more realistic predictions of ground deformations than individual models. Specifically, our results indicate that the Gonzalez-Sagaseta model outperforms other models in predicting ground surface settlements, while the Loganathan-Poulos model is most suitable for predicting subsurface vertical and horizontal deformations. Importantly, our analysis reveals that when monitoring data are sparse, model uncertainties may contribute up to 78.7% of the total uncertainties. Thus, obtaining sufficient data for parameter fitting is crucial for accurate predictions. The proposed method in this study offers a more realistic and efficient prediction of tunnelling-induced ground deformations.

The Fort d’Issy-Vanves-Clamart (FIVC) braced excavation in France is analyzed to provide insights into the geotechnical serviceability assessment of excavations at great depth within deterministic and probabilistic frameworks. The FIVC excavation is excavated at 32 m below the ground surface in Parisian sedimentary basin and a plane-strain finite element analysis is implemented to examine the wall deflections and ground surface settlements. A stochastic finite element method based on the polynomial chaos Kriging metamodel (MSFEM) is then proposed for the probabilistic analyses. Comparisons with field measurements and former studies are carried out. Several academic cases are then conducted to investigate the great-depth excavation stability regarding the maximum horizontal wall deflection and maximum ground surface settlement. The results indicate that the proposed MSFEM is effective for probabilistic analyses and can provide useful insights for the excavation design and construction. A sensitivity analysis for seven considered random parameters is then implemented. The soil friction angle at the excavation bottom layer is the most significant one for design. The soil-wall interaction effects on the excavation stability are also given.

BackgroundAmong diabetes mellitus (DM) patients, stress hyperglycemia ratio (SHR) is a strong predictor of short- and long-term prognosis, and adverse cardiovascular events. However, whether SHR is associated with increased risk of presence and severity of chronic kidney (CKD) disease remains undetermined.MethodsPatients with DM from the National Health and Nutrition Examination Survey (NHANES) database (1999–2020) were included and divided into 5 groups according to their SHR level (quintile 1 to 5). Study outcomes were CKD, advanced CKD (ACKD), and CKD severity. Logistic regression and restricted cubic spline (RCS) were used to assess the association between the SHR and outcomes.ResultsTotally, 6,119 patients were included. After adjustment, compared to patients with SHR in quintile 3 (as reference), the risk of CKD is 1.50 (P

Abstract Melanoma's high metastatic potential, especially to the brain, poses significant challenges to patient survival. The blood‒brain barrier (BBB) is a major obstacle to the effective treatment of melanoma brain metastases. We screened antipsychotic drugs capable of crossing the BBB and identified penfluridol (PF) as the most active candidate. PF reduced melanoma cell viability and induced apoptosis. In animal models, PF effectively inhibited melanoma growth and metastasis to the lung and brain. Using immunoprecipitation combined with high‐resolution mass spectrometry, and other techniques such as drug affinity responsive target stability, we identified CIP2A as a direct binding protein of PF. CIP2A is highly expressed in melanoma and its metastases, and is linked to poor prognosis. PF can restore Protein Phosphatase 2A activity by promoting CIP2A degradation, thereby inhibiting several key oncogenic pathways, including AKT and c‐Myc. Additionally, von Hippel‒Lindau (VHL) is the endogenous E3 ligase for CIP2A, and PF enhances the interaction between VHL and CIP2A, promoting the ubiquitin‒proteasome degradation of CIP2A, thereby inhibiting melanoma growth and metastasis. Overall, this study not only suggests PF's potential in treating melanoma and its brain metastases but also highlights CIP2A degradation as a therapeutic strategy for melanoma.

Sexual reproduction through seeds is an effective way to renew plant populations and increase their genetic diversity, but seed germination process is complicated and relatively difficult due to the restriction of environmental conditions. Wetland plants that reproduce sexually through seeds may be affected by changes in moisture and temperature. This study aims to explore the ecological adaptation strategies of seed germination of Lilium concolor var. megalanthum under different hydrothermal conditions. Controlled experiments were conducted to investigate the germination performance of L. concolor var. megalanthum seeds at different temperatures (10°C, 15°C, 20°C, 25°C, and 30°C) and simulated drought stress conditions using PEG-6000 solutions (0%, 5%, 10%, 15%, and 20%). The results showed that temperature, drought stress, and their interaction significantly affected the days to first germination, germination percentage, coefficient of germination rate, germination energy, germination index, and vigor index of seeds (p

BackgroundInsomnia (ISM) is one of the non-traditional drivers of atherosclerosis (AS) and an important risk factor for AS-related cardiovascular disease. Our study aimed to explore the shared pathways and diagnostic biomarkers of ISM-related AS using integrated bioinformatics analysis.MethodsWe download the datasets from the Gene Expression Omnibus database and the GeneCards database. Weighted gene co-expression network analysis and gene differential expression analysis were applied to screen the AS-related gene set. The shared genes of ISM and AS were obtained by intersecting with ISM-related genes. Subsequently, candidate diagnostic biomarkers were identified by constructing protein–protein interaction networks and machine learning algorithms, and a nomogram was constructed. Moreover, to explore potential mechanisms, a comprehensive analysis of shared genes was carried out, including enrichment analysis, protein interactions, immune cell infiltration, and single-cell sequencing analysis.ResultsWe successfully screened 61 genes shared by ISM and AS, of which 3 genes (IL10RA, CCR1, and SPI1) were identified as diagnostic biomarkers. A nomogram with excellent predictive value was constructed (the area under curve of the model constructed by the biomarkers was 0.931, and the validation set was 0.745). In addition, the shared genes were mainly enriched in immune and inflammatory response regulation pathways. The biomarkers were associated with a variety of immune cells, especially myeloid immune cells.ConclusionWe constructed a diagnostic nomogram based on IL10RA, CCR1, and SPI1 and explored the inflammatory-immune mechanisms, which indicated new insights for early diagnosis and treatment of ISM-related AS.

Phages and phage-encoded lytic enzymes are promising antimicrobial agents. In this study, we report the isolation and identification of bacteriophage KP2025 from Klebsiella pneumoniae. Bioinformatics analysis of KP2025 revealed a putative endolysin, LysKP213, containing a T4-like_lys domain. Purified LysKP213 was found to be highly thermostable, retaining approximately 44.4% of its lytic activity after 20 h of incubation at 95°C, and approximately 57.5% residual activity after 30 min at 121°C. Furthermore, when administered in combination with polymyxin B or fused at the N-terminus with the antimicrobial peptide cecropin A (CecA), LysKP213 exhibited increased antibacterial activity against Gram-negative pathogens, including K. pneumoniae, Pseudomonas aeruginosa, Acinetobacter baumannii, and Escherichia coli, both in vitro and in vivo. These results indicated that LysKP213 is a highly thermostable endolysin that, when combined with or fused with an outer membrane permeabilizer, has enhanced antibacterial activity and is a candidate agent for the control of infections by Gram-negative pathogens.